MEMBRANE POTENTIAL MEASUREMENTS IN ISLETS OF LANGERHANS FROM ob/ob OBESE MICE SUGGEST AN ALTERATION IN [Ca²⁺]_i-ACTIVATED K⁺ PERMEABILITY

¹ Department of Biophysics, School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ
² Laboratory of Cell Biology and Genetics, National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases, National Institutes of Health, Building 4, Room 312, Bethesda, MD 20205, U.S.A.

High-resistance micro-electrodes were used to measure membrane potentials in -cells from islets of Langerhans of ob/ob obese mice (Norwich colony). In the presence of glucose the burst pattern of electrical activity recorded in ob/ob -cells, although similar to the burst pattern recorded from normal -cells, presents important differences. The membrane potential of the ob/ob -cells in the presence of 11 mM glucose in the modified Krebs solution oscillates between a silent-phase level at -48 mV and an active-phase level at -36 mV, similarly to normal mouse islet -cells. However, the average active-phase duration is 20 s in ob/ob -cells compared with 5 s in normal -cells. The average burst frequency is 1·8 bursts/min in ob/ob -cells compared with 3 bursts/min in normal -cells. While normal -cells show continuous spike activity above 16 mM glucose, ob/ob -cells often exhibit a burst pattern of electrical activity at glucose concentrations as high as 33 mM. Compared with normal -cells, the relationship between spike frequency and glucose concentration is shifted towards lower concentrations in ob/ob -cells. Thus, the concentration for half-maximal spike frequency is 6·9 mM for the ob/ob -cells and 10·2 mM for the normal -cells. In ob/ob -cells, the mitochondrial inhibitor carbonyl-cyanide m-chlorophenylhydrazone induces hyperpolarization of the membrane, consistent with its effect of stimulating K⁺ permeability in normal islets. However, quinine and the sulphonylurea glibenclamide did not block the silent phase between the bursts of electrical activity. Both drugs block the [Ca²⁺]_i-activated K⁺ permeability thought to control the membrane potential at the silent phase in normal -cells. The modified pattern of response to glucose and decreased sensitivity to quinine and glibenclamide suggest that the -cell membrane of the ob/ob islet of Langerhans has a modified [Ca²⁺]_i-activated K⁺ permeability.

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